Intermediates for synthesizing BH4 and its derivatives

ABSTRACT

The present invention relates to intermediates for synthesizing BH 4  and derivatives thereof. The intermediates are shown as follows: ##STR1## wherein R 1  is a hydrogen atom, alkyl, aralkyl, or aryl group; R 2  is an alkyl, hydroxyalkyl, or polyhydroxyalkyl group; R 3  and R 4  are the same or different and represent alkyl, aralkyl, or aryl group; R 5 , R 6 , R 7 , and R 8  are the same or different and represent a hydrogen atom or acyl group; R 9  is an alkyl, aralkyl, or aryl group; R 10  and R 11  are the same or different and represent a hydrogen atom or acyl group; n is an integer of 5 or less; and HX is an acid. The invention also relates to a process for the preparation of L-biopterin.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to intermediates for synthesizing BH₄ andits derivatives, as well as to a process for the preparation ofL-biopterin.

2. Related Arts

The compound BH₄, namely, 5,6,7,8-tetrahydro-L-erythrobiopterin, is oneof the coenzymes of aromatic amino acid hydroxylase, is an indispensablecompound for biosynthesis of dopamine, noradrenalin, adrenaline, andmelatonin, and is reprsented by the following formula: ##STR2##

A deficiency of BH₄ causes serious neurological disorders like atypicalphenylketonuria and Parkinsonism: and recently, it has been found thatsymptoms due to such diseases can be remarkably improved byadministration of BH₄. Further, it has been recognized that BH₄ iseffective for curing infantile autism and depressions.

Since BH₄ has such useful pharmacological activities, various studieshave been made for the synthesis thereof, and are referenced as follows:E. L. Patterson et al. "J. Am. Chem. Soc." Vol. 78, page 5868 (1956); H.Rembold et al. "Chem. Ber." Vol. 96, page 1395 (1963); E. C. Taylor etal. "J. Am. Chem. Soc." Vol. 98, page 2301 (1976); M. Viscontini et al."Helv. Chim. Acta" Vol. 52, page 1225 (1969); ibid., Vol. 55, page 574(1972); ibid., Vol. 60, page 211 (1977); ibid., Vol 62, page 2577(1979); K. J. M. Andrews et al. "J. Chem. Soc." (c), page 928 (1969); S.Matsurra et al. "Bull. Chem. Soc. Jpn." Vol. 48, page 3767 (1975);ibid., Vol. 52, page 181 (1979); "Chem. Lett." page 735 (1984); Jap.Pat. No. 59-21685(A); ibid., 59-82091(A); and ibid., 60-204786(A).

Each of the conventional processes for preparing BH₄ has severaldrawbacks in that an expensive saccharide is required as startingmaterial to provide the asymmetric carbon atom at its side-chain, thatyield and purity will become low due to multi-reaction steps, throughunstable intermediates that require troublesome treatment operations,and that it requires troublesome purification procedures. Therefore, theconventional processes are unsuitable for industrial production of thecompound and its derivatives.

SUMMARY OF THE INVENTION

The present inventors have energetically worked to develop a process forpreparing BH₄, one which can be applied for a commercial and convenientproduction thereof, by taking the following points into consideration:

(a) The starting material is available at reasonable cost,

(b) The number of synthetic steps can be made minimum,

(c) Good yield can be attained, and

(d) If possible, it can be applied for synthesizing compounds analogousto BH₄.

As a result, they have found that a tetrahydrofuranylpyrimidinederivative of the formula ##STR3## wherein R₁ is a hydrogen atom, alkyl,aralkyl, or aryl group; R₂ is an alkyl, hydroxyalkyl, orpolyhydroxyalkyl group; R₃ and R₄ are the same or different andrepresent alkyl, aralkyl or aryl group.

is suitable as an intermediate for synthesizing BH₄ and analogouscompounds thereof to open the way for the present invention.

The following are steps for synthesizing the tetrahydrofuranylpyrimidinederivatives shown by said Formula I as well as BH₄ and its analogouscompounds: ##STR4## wherein R₁, R₂, R₃, and R₄ have the meanings asalready stated; R₅, R₆, R₇, and R₈ are the same or different andrepresent a hydrogen atom or acyl group; R₉ is an alkyl, aralkyl or arylgroup; n is an integer of 5 or less; and HX is an acid.

In connection with the compounds, the definitions of each substituentshall generally be given as follows: The alkyl group may be of methyl,ethyl, propyl, butyl, pentyl, hexyl group, isomers thereof or the like.The aralkyl group may be of benzyl, xylyl, phenethyl group or the like.The aryl group may be of phenyl, tolyl, anisoyl, naphthyl group or thelike. The hydroxyalkyl group may be of hydroxymethyl, hydroxyethyl,hydroxypropyl group or the like. The polyhydroyalkyl group may be of1,2-dihydroxyethyl, 1,2-dihydroxypropyl, 2,3-dihydroxypropyl,1,2,3-trihydroxpropyl group or the like.

The tetrahydrofuranylpyrimidine derivative (I) can be prepared byreacting 2,4,5-triaminopyrimidine derivative (VIII) with anepoxy-tetrahydrofuran derivative (IX).

The tetrahydrofuranylpyrimidine derivative (I) can be converted intodihydropteridine derivative (III') or tetrahydropteridine derivative(IV') by hydrolyzing its acetal portion with an acid, and by ringclosing at the amino group portion. The dihydropteridine derivative(III') can be converted into pteridine derivative (V') by oxidizing itspteridine ring, or into acyl-dihydropteridine derivative (III") throughan acylation. the acyl-dihydropteridine derivative (III") can easily bechanged by treating with an alcohol into acyl-tetrahydropteridinederivative (IV") which can, in turn, be converted again into thedihydropteridine derivative (III') by treating the same with an acid.While, the tetrahydropteridine derivative (IV') can be transformed intodihydropteridine derivative (III') by treating the same with an acid, orinto acyltetrahydropteridine derivative (IV") through an acylationthereof.

The pteridine derivative (V') can be converted into biopterin derivative(VI) by reducing the carbonyl group in its side-chain. This reductioncan be carried out with the use of sepiapterin reductase in the manneras described by S. Katoh et al. "Biochem. Biophys. Res. Commun." Vol.118, page 859 (1984), or with use of a conventional reducing reagent. Inthis connection, a conversion from the biopterin derivative (VI) totetrahydrobiopterin derivative (VII) has already been reported invarious papers, for instance, S. Matsuura et al. "Chem. Lett." page 735(1984), and Jap. Pat. No. 59-21685 (A), 59-82091(A) and 60-204786(A).

According to the invention, L-biopterin can be prepared by treatingbiopterin derivative (V'-a), wherein R₁ [of (v')] is a hydrogen atom,and R₂ is a methyl group, with sepiapterin redutase. In connection withthis, please note that the reduction of2-amino-4-hydroxy-6-(1'-hydroxy-2'-oxopropyl)pteridine (V'-a) shall, ingeneral, produce four compounds; but according to the invention,L-biopterin (compound 1) can only and unexpectedly be formed with astereospecificity. ##STR5##

In the above synthetic procedures, BH₄ can be prepared as the finalproduct (VII), when R₁ is a hydrogen atom and R₂ is a methyl group.Neopterin is also synthesized by this procedure, when R₁ is a hydrogenatom and R₂ is a hydroxymethyl group. Therefore, BH₄ and its analogouscompounds can be synthesized easily and at a reasonable cost, when thecompounds according to the invention are utilized as an intermediatetherefor.

PREFERRED EMBODIMENTS OF THE INVENTION

The invention will now be further explained in more detail withreference to Examples.

EXAMPLE 1 (a) 2,5-Dihydro-2,5-dimethoxy-2-methylfuran

To a mixture of 2-methylfuran (123 g, 1.50 mol), sodium carbonate (318g, 3.00 mol) and methanol (2180 ml) cooled at -75° C. under stirring ina dry ice/acetone bath, dichloromethane (87.9 ml) containing bromine(240 g, 1.50 mol) was added dropwise over 4 hours.

After completion of the addition, the reaction mixture was removed fromthe bath and allowed to come to room temperature; it was then filteredto remove sodium bromide. Saturated sodium chloride solution was addedto the filtrate, wich was extracted with dichloromethane 3 times. Thecombined dichloromethane layer was washed twice with saturated sodiumchloride solution and dried over anhydrous sodium sulfate. The resultingsolution was concentrated in a water bath kept at 50° C. or less anddistilled in vacuo to afford 171 g (79.1%) of the titled compound.

Boiling point: 54° C. (bp₁₄)

¹ H-NMR spectrum (CDCl₃, δppm): 1.51, 1.57: (3H, s×2, --CH₃), 3.12,3.20: (3H, s×2, --OCH₃), 3.43, 3.50: (3H, s×2, --OCH₃), 5.48, 5.76: (1H,proton at 5-position), 5.96: (2H, m, olefinic proton).

Silica gel TLC: Rf=0.53, 0.59 (hexane:ethyl acetate=5:1).

(b) 3,4Epoxy-2,5-dimethoxy-2-methyltetrahydrofuran

To a mixture of 2,5-dihydro-2,5-dimethoxy-2-methylfuran (21.6 g, 150mmol), benzonitrile (17.0 g, 165 mmol), and methanol (40 ml) heated at40° C., 31% aqueous solution of hydrogen peroxide (11.0 g, 100 mmol) wasadded dropwise over 2.5 hours, while maintaining pH in a range of 7.50to 8.00 by addition of an aqueous solution of sodium hydroxide. Then themixture was further reacted for 17.5 hours, while maintaining thetemperature at 60° C. and pH in the range of 7.50 to 8.00.

After confirmation of the exhaustion of the peroxide by iodometry, thereaction mixture was cooled to room temperature, 60 ml of water wasadded to it, and it was extracted three times with chloroform. After theextract was washed with water three times, pentane was added to thechloroform layer to remove benzamide. The resulting filtrate wasconcentrated to obtain a crude product (30.7 g), which was subjected tosilica gel chromatography (elution solvent, hexane:ethyl acetate=6:1),so as to afford 2.21 g (9.2%) of the titled compound.

¹ H-NMR spectrum (CDCl₃ δppm): 1.51: (3H, s, --CH₃), 3.33: (3H, s,--OCH₃), 3.47: (1H, d, J=2.7 Hz, proton at 3-position), 3.52: (3H, s,--OCH₃), 3.67: (1H, br.d, J=2.7 Hz, proton at 4-position), 5.10: (1H,br.s, proton at 5-position).

Silica gel TLC: Rf=0.47 (hexane:ethyl acetate=2:1).

(c)2,4-Diamino-6-hydroxy-5-[4'-(3'-hydroxy-2',5'-dimethoxy-2'-methyltetrahydrofuranyl)]pyrimidine

To a suspension of 2,4,5-triamino-6-hydroxypyrimidine sufate (8.66 g,36.2 mmol) in ethanol (18 ml), sodium carbonate (7.69 g, 72.5 mmol)dissolved in distilled water (72.5 ml) was added. After completion ofbubbling with carbon dioxide gas,3,4-epoxy-2,5-dimethoxy-2-methyltetrahydrofuran (2.90 g, 18.1 mmol)dissolved in ethanol (18.3 ml) was added, and the resulting mixture washeated to 100° C. under nitrogen atmosphere to react for 69 hours.

After the mixture was cooled to room temperature, methanol (50 ml) wasadded to it and solids were removed by filtration. After concentrationof the filtrate, methanol (50 ml) was added and then insoluble matterwas filtered off. The resulting filtrate was concentrated to obtain acrude product which was, in turn, subjected to latrobeads columnchromatography (elution solvent, methanol) to afford 2.94 g (53.9%) ofthe titled compound.

¹ H-NMR spectrum (pyridine-D₅, δppm): 1.74: (3H, s, --CH₃), 3.44: (3H,s, --OCH₃), 3.49: (3H, s, --OCH₃), 3.81: (1H, m, proton at 4'-position),4.71: (1H, br.d, J=6 Hz, proton at 3'-position), 5.38: (1H, br.d, J=5Hz, proton at 5'-position).

¹³ C-NMR spectrum (DMSO-D₆, δppm): 19.4, 48.1, 55.2, 70.1, 77.2, 98.1,107.0, 108.0, 152.2 160.9, 161.4.

IR spectrum (KBr, cm⁻¹): 3328, 1588.

MS spectrum (EI): 301 (M⁺), 269.

Silica gel TLC: Rf=0.27 (chloroform:methanol=5:1).

EXAMPLE 22-Amino-4-hdyroxy-7-methoxy-6-(1'-hydroxy-2'-oxopropyl)-5,6,7,8-tetrahydropteridine

To2,4-diamino-6-hydroxy-5-[4'-(3'-hydroxy-2',5'-dimethoxy-2'-methyltetrahydrofuranyl)]pyrimidine(70 mg, 0.232 mmol) obtained by the process described in Example 1,acetic acid (3.0 ml) was added, and the mixture was stirred at 50° C.for 20 minutes. After being cooled to room temperature, the reactionmixture was dried in vacuo to obtain a crude product which was, in turn,subjected to silica gel thin-layer chromatography (developing solvent,chloroform:methanol=5:1) to afford 17.6 mg (28.2%) of the titledcompound.

¹ H-NMR spectrum (DMSO-D₆, δppm): 2.22: (3H, s, --CH₃), 3.03: (1H, m,proton at 6-position), 3.49: (3H, s, --OCH₃), 4.13: (1H, br.t, proton at1'-position), 4.88: (1H, d, J=6 Hz, proton at 7-position), 5.69: (1H,br.d, J=6 Hz, hydroxy proton at 1'-position),

¹³ C-NMR spectrum (DMSO-D₆, δppm): 26.6, 55.6, 55.7, 74.4, 96.9, 98.5,155.9, 157.7, 158.1 210.4.

MS spectrum (EI): 269 (M⁺), 196.

Silica gel TLC: Rf=0.48 (chloroform:methanol=5:1).

EXAMPLE 31-Acetamido-5-acetyl-4-hydroxy-7-methoxy-6-(1'-hydroxy-2'-oxopropyl)-5,6,7,8-tetrahydropteridine

To2,4-diamino-6-hydroxy-5-[4'-(3'-hydroxy-2',5'-dimethoxy-2'-methyltetrahydrofuranyl)]pyrimidine(220 mg, 0.730 mmol) obtained by the process described in Example 1, 6Nhydrochloric acid (2.20 ml) was added, and the mixture was stirred for10 minutes at room temperature and then concentrated in vacuo. After theconcentrate was cooled on ice, acetic anhydride (3.50 ml) and pyridine(3.50 ml) were added and allowed to react for 1 hour at room temperatureunder stirring. After removal of insoluble matter by filtration, thefiltrate was poured into ether (60 ml), and the semi-solid material thatappeared was collected by decantation. The material was then washedthree times with ether and dried in vacuo. To the dried material,methanol (7 ml) was added and allowed to react for 30 minutes at roomtemperature under stirring. The reaction mixture was subjected to silicagel thin-layer chromatography (developing solvent,chloroform:methanol=5:1) to afford 73.9 mg (28.8%) of the titledcompound.

¹ H-NMR spectrum (DMSO-D₆, δppm): 1.96, 1.99, 2.14: (3H×3, s×3, CH₃CO×2, --CH₃), 3.19: (3H, s, --OCH₃), 4.58: (1H, br.d, J=4.5 Hz, protonat 7-position), 4.86: (1H, d, J=7.3 Hz, proton at 1'-position), 5.22:(1H, br.d, J=7.3Hz, proton at 6-position), 7.91: (1H, br.d, J=4.5 Hz,proton at 8-position).

¹³ C-NMR spectrum (DMSO-D₆, δppm): 20.2, 21.7, 26.5, 47.5, 53.5, 74.7,81.9. 92.7, 153.0 153.3, 157.4, 169.5, 171.0, 204.1.

IR spectrum (KBr, cm⁻¹): 3344, 1710, 1616.

Silica gel TLC: Rf=0.27 (chloroform:methanol=5:1).

EXAMPLE 42-Acetamido-4-hydroxy-7-methoxy-6-(1'-acetoxy-2'-oxopropyl)-5,6,7,8-tetrahydropteridine

To2,4-diamino-6-hydroxy-5-[4'-(3'-hydroxy-2',5'-dimethoxy-2'-methyltetrahydrofuranyl)]pyrimidine(150 mg, 0.498 mmol) obtained by the process described in Example 1,acetic acid (1.5 ml) was added, and the mixture was stirred for 20minutes at 50° C. After being cooled to room temperature, the reactionmixture was dried in vacuo. A part of the dried substance was taken andsubjected to ¹ H-NMR spectroscopy to confirm the formation of2-amino-4-hydroxy-7-methoxy-6-(1'-hydroxy-2'-oxopropyl)-5,6,7,8-tetrahydropteridine(see Example 2).

After the other part was ice-cooled, acetic anhydride (2.5 ml) andpyridine (2.5 ml) were added, and the mixture was stirred for 1 hour atroom temperature; then ether (50 ml) was added. The resulting solidmaterial was collected by filtration and washed with ether to obtain94.1 mg of a crude product which was subjected to silica gel thin-layerchromatography (developing solvent, chloroform:methanol=5:1) to afford20.0 mg (11.4%) of the titled compound.

¹ H-NMR spectrum (DMSO-D₆, δppm): 2.01, 2.10, 2.17: (3H×3, s×3, CH₃CO×2, --CH₃), 3.42: (3H, s, --OCH₃), 3.83: (1H, m, proton at6-position), 4.86: (1H, br.d, J=6.8 Hz, proton at 5-position), 5.18:(1H, d, J=2.0 Hz, proton at 7-position), 5.28: (1H, d, J=3.4 Hz, protonat 1'-position).

¹³ C-NMR spectrum (DMSO-D₆, δppm): 20.3, 24.1, 27.0, 52.4, 55.3, 77.7,96.6, 103.6, 148.3 152.4, 155.0, 168.9, 169.6, 203.9.

MS spectrum (EI): 353 (M⁺).

Silica gel TLC: Rf=0.45 (chloroform:methanol=5:1).

EXAMPLE 52-Amino-4-hydroxy-6-(1'-hydroxy-2'-oxopropyl)-5,6-dihydropteridine

To2,4-diamino-6-hydroxy-5-[4'-(3'-hydroxy-2',5'-dimethoxy-2'-methyltetrahydrofuranyl)]pyrimidine(10 mg, 0.033 mmol) obtained by the process described in Example 1, 6Nhydrochloric acid (100 μl) was added, and the mixture was stirred for 10minutes at room temperature and immediately concentrated in vacuo toafford 9 mg of the titled compound as crude product.

This substance exists in the following chemical equilibrium inhydrochloric acid solution: ##STR6##

¹ H-NMR spectrum (20% DCl, δppm): 2.51, 2.54: (3, s×2, --CH₃), 4.17,4.37: (1H, br.d, br.s, J=7 Hz, proton at 6-position), 4.88: (br.d, J=7Hz, proton at 1'-position), 5.65, 5.74: (1H, br.s×2, proton at7-position).

IR spectrum (KBr, cm⁻¹): 3260, 1650.

MS spectrum (FAB, positive) 238 [(M+H)⁺ ], 165.

EXAMPLE 61-Amino-4-hydroxy-6-(1'-hydroxy-2'-oxopropyl)-5,6-dihydropteridine

To2-amino-4-hydroxy-7-methoxy-6-(1'-hydroxy-2'-oxopropyl)-5,6,7,8-tetrahydropteridine(30 mg, 0.10 mmol) obtained by the process described in Example 2, 6Nhydrochloric acid (600 μl) was added, and the mixture was stirred for 10minutes at room temperature and concentrated in vacuo to afford 23 mg ofthe titled compound as crude product.

Physico-chemical data of this compound were the same as those disclosedin Example 5.

EXAMPLE 72-Acetamido-5-acetyl-4-hydroxy-6-(1'-hydroxy-2'-oxopropyl)-5,6-dihydropteridine

To2,4-diamino-6-hydroxy-5-[4'-(3'-hydroxy-2',5'-dimethoxy-2'-methyltetrahydrofuranyl)]pyrimidine(220 mg, 0.730 mmol) obtained by the process described in Example 1, 6Nhydrochloric acid (2.20 ml) was added, and the mixture was stirred for10 minutes at room temperature and then dried in vacuo. After thematerial was cooled on ice, acetic anhydride (3.50 ml) and pyridine(3.50 ml) were added to the concentrate and allowed to react for 1 hourunder stirring. After insoluble matter was filtered off, the filtratewas poured into ether (60 ml), and the resulting semi-solid material wasobtained by decantation, which material was washed three times withether and dried in vacuo to afford 400 mg of the titled compound ascrude product.

¹ H-NMR spectrum (pyridine-D₅, δppm): 2.15, 2.34, 2.54: (3H×3, s×3, CH₃CO×2, --CH₃), 5.62: (1H, d, J=8 Hz, proton at 1'-position), 5.96: (1H,br.s, prton at 7-position), 6.24: (1H, br.d, J=8 Hz, proton at6-position).

MS spectrum (FAB, positive): 322 [(M+H)⁺ ].

EXAMPLE 82-Amino-4-hydroxy-6-(1'-hydroxy-2'-oxopropyl)-5,6-dihydropteridine

To2-acetamido-5-acetyl-4-hydroxy-7-methoxy-6-(1'-hydroxy-2'-oxopropyl)-5,6,7,8-tetrahydropteridine(10 mg, 0.028 mmol) obtained by the process described in Example 3, 6Nhydrochloric acid (300 μl) was added, and the mixture was stirred for 6hours at room temperature and then concentrated in vacuo to afford 6.5mg of the titled compound as crude product.

This compound gave physico-chemical data the same as those listed inExample 6.

EXAMPLE 9 2-Amino-4-hydroxy-6-(1'-hydroxy-2'-oxopropyl)pteridine

To2,4-diamino-6-hydroxy-5-[4'-(3'-hydroxy-2',5'-dimethoxy-2'-methyltetrahydrofuranyl)]pyrimidine(200 mg, 0.664 mmol) obtained by the process described in Example 1, 6Nhydrochloric acid (2.00 ml) was added, and the mixture was stirred for10 minutes at room temperature. A part of the reaction mixture wastaken, concentrated to dryness in vacuo and checked by ¹ H-NMRspectroscopy to confirm the formation of2-amino-4-hydroxy-6-(1'-hydroxy-2'-oxopropyl)-5,6-dihydropteridine (seeExample 5).

The remaining reaction solution was added to a suspension of iodine (600mg, 2.36 mmol) in methanol (2.00 ml) and methanol (1.00 ml) was furtheradded thereto.

After the reaction had proceeded for 10 minutes at room temperature,distilled water (5.00 ml) was added. Then neutralization was achievedwith sodium carbonate (764 mg, 7.21 mmol), and then distilled water (10ml) was added to the reaction mixture to obtain a dark brown solid thatwas collected by filtration. The solids were washed with water followedby methanol and dried in vacuo to afford 99.2 mg (63.5%) of the titledcompound, as pale yellow solids.

¹ H-NMR spectrum (DMSO-D₆, δppm): 2.18: (3H, s, --OCH₃), 5.24: (1H, d,J=6 Hz, proton at 1'-position), 6.33: (1H, d, J=6 Hz, hydroxy proton at1'-position), 6.96: (2H, br.s, amino proton at 2-position), 8.71: (1H,s, proton at 7-position).

IR spectrum (KBr, cm⁻¹): 3248, 1652.

mili-MS spectrum: C₉ H₉ N₅ O₃, 235 (M⁺), 219, 192, 177, 163, 136, 122.

EXAMPLE 10 L-Biopterin

To 2-amino-4-hydroxy-6-(1'-hydroxy-2'-oxopropyl)pteridine (23.6 mg, 100μmol) obtained by the process described in Example 9, in distilled water(100 ml), β-nicotinamide adenine dinucleotide phosphate (reduced type)(167 mg) dissolved in 0.2M phosphate buffer (pH 6.4, 100 ml) was added.One unit of sepiapterin reductase from rat erythrocytes partiallypurified by the method described by Sueoka et al. ["Biochim. Biophys.Acta" Vol. 717, page 265 (1982)] was added to the mixture. The resultingsolution was incubated for 5 hours at 30° C. with shaking,ultrafiltered, and freeze dried. The freeze dried material was dissolvedin a mixture of 0.1N acetic acid/MeOH (95/5, V/V) and purified byhigh-performance liquid chromatography using a Develosil ODS column. Thesolvent was removed from the resulting L-biopterin-containing fractionsto obtain a residue which was suspended in a small amount of distilledwater and freeze-dried to afford 10.5 mg (44%) of the desired compound,as pale yellow powder.

[α]_(D) ²⁵ =-60° (c=0.13, 0.1N-HCl).

UV spectrum (0.1N-HCl) λ_(max) nm: 210, 247, 320.

¹ H-NMR spectrum (DMSO-D₆, δppm): 1.06: (3H, d, J=6 Hz, --CH₃), 3.92:(1H, m, 2'-H), 4.44: (1H, dd, J=5 Hz, 5 Hz, 1'-H), 4.69: (1H, d, J=5 Hz,2'-OH), 5.58: (1H, d, J=5 Hz, 1'-OH), 6.86: (2H, s, 2-NH₂), 8.71: (1H,s, 7-H), 11.42: (1H, br.s, 3-NH).

Said value of specific rotation is substantially the same as thatreported by B. Green et al. ["Chem. Ber." Vol. 99, page 2162 (1966)],and the values of UV and NMR spectra coincide with those of standardsamples.

We claim:
 1. A dihydropteridine compound of the formula ##STR7## whereinR₁ is hydrogen, C₁ -C₆ alkyl, benzyl, xylyl, phenethyl, phenyl, tolyl,anisoyl or naphthyl; R₂ is C₁ -C₆ alkyl, hydroxy C₁ -C₃ alkyl orpolyhydroxy C₂ -C₃ alkyl; R₅, R₆ and R₇ are the same or different andrepresent hydrogen or alkanoyl; n is zero or an integer of 5 or less;and HX is an acid.
 2. A tetrahydropteridine compound of the formula##STR8## wheren R₁ is hydrogen, C₁ -C₆ alkyl, benzyl, xylyl, phenethyl,phenyl; tolyl, anisoyl or naphthyl; R₂ is C₁ -C₆ alkyl, hydroxy C₁ -C₃alkyl or polyhydroxy C₂ -C₃ alkyl; R₅, R₆, R₇ and R₈ are the same ordifferent and represent hydrogen or alkanoyl; and R₉ is C₁ -C₆ alkyl,benzyl, xylyl, phenethyl, phenyl, tolyl, anisoyl or naphthyl; n is zeroor an integer of 5 or less; and HX is an acid.
 3. A pteridine compoundof the formula ##STR9## wherein R₁ is hydrogen, C₁ -C₆ alkyl, benzyl,xylyl, phenethyl, phenyl, tolyl, anisoyl or naphthyl; R₂ is C₁ -C₆alkyl, hydroxy C₁ -C₃ alkyl or polyhydroxy C₂ -C₃ alkyl; R₁₀ and R₁₁ arethe same or different and represent hydrogen or alkanoyl; n is zero oran integer of 5 or less; and HX is an acid.